The airway extending from the nasal cavity, oral cavity to the pharynx, larynx, trachea, bronchia, bronchioles, and alveoli is a passageway for expiratory and inspiratory air.
In the airway, there occur many diseases such as nasal allergies, asthma, bronchitis, lung emphysema, and the like. The method for administering a medicament in the pharmacotherapy for these diseases may be classified into the whole body administration such as the use of orally administered medicaments and injections, and intratracheobronchial local administration such as the use of nebulas, inhalants, and the like.
Oral administration is an easy method, and the use of injections ensures the absorption of the injections into the body, and therefore, these administering methods have widely been employed. However, intratracheobronchial administration of a medicament is highly valuable in the light of convergence of the medicament into an acting site, reduction of adverse side effects due to the convergence, and fast-acting properties of the effect of the medicament.
Further, in addition to the local administration of a medicament for such diseases as mentioned above, which occur in the airway, there has recently been a trial of proceeding a medicament from alveoli to blood by utilization of the fact that the barrier between the alveoli and blood is dwarfish, and the intratracheobronchial administration has now attracted public attention as a systemic administration method for peptides, proteins or the like, which are metabolized in the gastrointestinal tract, liver or the like so as to be inactivated, when these are orally administered.
In addition, there have been attempts to locally administer a vaccine in the airway by utilizing the antigen recognizing function of the lymphatic system in the airway, so as to prevent and treat a disease. Therefore, it may be said that the importance of intratracheobronchial administration is very significant.
The preparations for intratracheobronchial administration to be used for the above intratracheobronchially administering method can be classified into the following two kinds, with respect to the properties of the particles of the preparations: (1) preparations, the droplets of which are deposited to the inside of the airway, and (2) preparations, the fine solid particles of which are deposited to the inside of the airway.
A preparation (1) is usually an aqueous solution containing a medicament, which is atomized by a nebulizer, and inhaled into the airway as minute droplets. Preparations (2) are further roughly classified into (i) aerosol preparations, in which the fine solid particles are contained in a pressure container in a state such that they are dispersed in a fluorohydrocarbon, and when they are discharged out of the vessel in the case of the use thereof, these particles move in the airway together with the fluorohydrocarbon, and after the fluorohydrocarbon has rapidly evaporated, they are finally deposited in the airway, as fine solid particles of the medicaments, and (ii) powder preparations in which a medicament is contained as fine solid particles in receptacle, and in the case of using any of them, the fine solid particles of the medicament are inhaled into the airway directly from the container or by use of an administration utensil, by injection or inhalation of breath, and deposited to the inside of the airway as fine solid particles of the medicament.
These preparations have already been put to practical use, regarding all the types thereof. The liquid preparations of (1) require a nebulizer or atomizer and are therefore, not convenient to carry. The fluorohydrocarbon aerosol preparations of (2)-(i) are simple to handle, and have been widely used, but there has arisen a trend of public opinion to restrict the use of these preparations, considering the problem of air pollution from fluorohydrocarbon gases. Under such circumstances, powder preparations for intratracheobronchial administration of (2)-(ii), which have remained comparatively backward in the development as compared with the other two kinds of preparations, have come to noticeably attract public attention.
In order to administer a powder preparation for intratracheobronchial administration, a receptacle for the powder preparation and an administering utensil are needed. In the following, the "receptacle" means a receptacle in which the powder preparation is directly contained, and the powder preparation is contained in the receptacle, after it has been prepared by mixing and stored until it is used. Therefore, the receptacle is ordinarily tightly sealed. In addition, the administering utensil in the present invention is generally a device for taking the powder preparation out of the above-mentioned receptacles containing the powder preparation in such a state as can be administered into the airway; it is, e.g., a device for maintaining the tightly sealed powder preparation at a proper position, and boring a hole in the receptacle so as to enable the powder preparation to proceed into the airway. The receptacle and administering utensil are usually separately produced, but they may be produced as an integrated product. For example, a part of a receptacle is removed when using the powder preparation, so as to produce a hole, whereby it becomes possible to cause the powder preparation contained in the receptacle to move into the respiratory tract from the receptacle.
The powder preparation, which has been made movable into the airway from the receptacle by use of an administering utensil or by performing some operations in an integrated product of a receptacle and administering utensil, is delivered into the airway by utilization of the inhalation of the breath of the user (patient) or of a gas from a pressurized gas cylinder or by some other device.
The receptacle and administering utensil for the powder preparation for intratracheobronchial administration are classified into the following two types according to the dose of the powder preparation in the receptacle: (i) a type in which the dose of the powder preparation to be delivered into the airway per one time has preliminarily been set apart and contained in each receptacle (unit dose type), and (ii) a type in which a multidose of the powder preparation is contained in the receptacle, and dose of the powder preparation is divided up by some means and sent into the airway every time the preparation is to be used (multidose type).
For the above two types of containing systems, there have been devised many administering utensils, and as specific examples thereof, there may be mentioned, e.g., as a unit dose type, the powder medicine-dispensing device disclosed in Japanese Examined Patent Publication (Kokoku) No. 63-6024, "Spinhaler" (Registered Trade Mark), "Rotahaler" (Registered Trade Mark), "Diskbaler" (Registered Trade Mark) or the like described in "Respiratory Drug Delivery" edited by P. R. Byron, published by CRC Press, 1990, p.169, and as a multidose type, "Turbohaler" (Registered Trade Mark) described on p.169 of the same publication, and the like.
The shapes of receptacles for containing a powder preparation vary in many ways depending on the above containing systems or the structure of the administering utensils. As the unit dose type receptacles, there have hitherto been known, e.g., hard medical capsules which have been widely used for oral preparations; disk-shaped molded products which can be charged in a "Diskhaler" (Registered Trade Mark); and disposable receptacles as proposed in WO 89/01348 Specification. In addition, as multidose type receptacles, there have been known the receptacles of such shapes as can be changed in conformity with the structure of an administering utensil and a predetermined amount of the content of the receptacle can be moved from the administering utensil to the airway. In the present invention, there may be used any of the receptacles of these shapes. In addition, a receptacle may constitute a part of an administering utensil. For example, a receptacle may be cylindrical and, simultaneously, have a structure such that the receptacles can be removed from its cap and fixed to an administering utensil by driving a screw.
On the other hand, with respect to the material of a receptacle containing the powder preparation, even if the present powder preparation is in the form of an inhalant that is administered into the airway of the human body, the receptacles are in direct contact with the powder preparation. Accordingly, as the materials which have specifically been known as those of the receptacles containing powder preparations, in consideration of safety and the like, there may be mentioned, as unit dose type ones, hard gelatin medical capsules which have widely been used for oral preparations; aluminium to be molded into a disk-shaped product (see e.g.p.169 of the above-mentioned publication published by R. Byron); or plastics, mainly polyolefinic ones such as polyethylene, polypropylene, and polystyrene, which have been proposed for disposable receptacles. In addition, as the materials of multidose type receptacles, there may be mentioned plastics, mainly polyolefinic ones such as polyethylene, polypropylene, and polystyrene; aluminium; glass; and the like.
As the powder preparations to be contained in the receptacles made of various materials, there have been known powder of a medicament itself alone, which is administered into the airway and deposited thereto, whereupon the effect of the medicine is exhibited at an affected part or the preparation is transferred to the whole body from the affected part and the effect of the medicines exhibited in the whole body, or mixtures thereof with an appropriate diluent, e.g. lactose, mannitol, crystallite cellulose and the like.
With respect to such a powder preparation for intratracheobronchial administration, since it is necessary to reach a target region with good efficiency and broaden the deposited area at the reached region, the particle diameter of the powder should be reduced. The interrelation between the particle diameter of the particles and the region attained by the preparation has been examined by many investigators, and though their reported values are not always consistent with other, it is said that, for example, particles with a particle diameter larger than 10 .mu.m, but up to about 500 .mu.m, are deposited mainly in the oral cavity and nasal cavity, particles with a particle diameter above 2 .mu.m and not more than 10 .mu.m are deposited mainly in the trachea, bronchi, and bronchioles and those having a particle diameter ranging from 0.5 to 2 .mu.m are deposited mainly in the alveoli. (see "The Newest Biopharmacology" edited by Awazu and Koizumi, published by Nankodo Publishers, 1991, p.67). The above-mentioned particle size is applied to a medicament particle alone in the powder preparation and a particle comprising a medicament, but not to an additive particle.
According to the technique regarding the above powder preparation for intratracheobronchial administration, the present inventors have continued their studies concerning the administration of powder medicaments into the nasal cavity, bronchi, alveoli or the like, and been confronted with significant technical problem on the basis of the fact that the above-mentioned powder preparation is a powder of fine particles.
That is, it has been found that, while a powder preparation is contained in the above-mentioned various receptacles and stored, or while it is charged in administering utensils, the powder preparation comes in contact with the receptacle owing to vibration, so that the fine particles of a medicament or fine particles comprising a medicament become adsorbed and adhered to the receptacle surfaces. It has been also found that when administering a medicament into the airway, even if the powder preparation contained in the receptacles is introduced into the airway by utilization of a gas pressurized by inhaled breath or some means, the fine particles adsorbed and adhered to the receptacle inner surfaces remain in the receptacles as such, so that the preparation does not reach the airway.
The above problem is quite insignificant, in the case of an oral preparation, which is to be administered together with the receptacles containing said preparation, even if the preparation is adsorbed and adhered to the inner surfaces of the receptacles, but in the case of a powder preparation for intratracheobronchial administration, in which the contents alone of the receptacles, not the receptacles themselves, are administered into the interior of the body, the amount of delivered content into the body is reduced, the problem becomes such a serious problem as may give an influence to the therapeutic effect of the preparation.
As a means of settling the present problem, there have hitherto been examined usually conceivable methods, such as a method of making fine particles, e.g. a method of enlarging the density of the powder preparation, a method of preliminarily adhering and adsorbing especially fine particles of the powder preparation to comparatively larger particles in the powder preparation, and the like, and it has been made clear that some methods are effective and the present problem has been settled e.g. in the case of corticosteroid preparation for intranaso-oral spraying administration. However, even if any of the above-mentioned methods is employed, depending upon the kind of a medicament, e.g. in peptides and proteins which exhibit noticeable absorptivity and adhesion properties to gelatin or plastics, there cannot be avoided adhesion and adsorption thereof to receptacles. In addition, when the powder preparation is kept under dried conditions especially for improvement of the physicochemical stability, it is very difficult, according to the above method, to prevent the powder preparation from being adhered and adsorbed to the receptacles.
Therefore, there have been demanded preparations for intratracheobronchial administration, which do not require troublesome formation of fine particles, which may be applied to various medicaments, and which are not adsorbed or adhered to the internal surfaces of the receptacles. There have been demanded also preparations for intratracheobronchial administration, which are not adsorbed or adhered to the inner surfaces of the receptacles, even under dried conditions.
Incidentally, the technical concept of employing hydroxypropyl methyl cellulose or the like as the material of receptacles for a medicament is already known. For example, Japanese Unexamined Patent Publication No. 61-100519 discloses medical hard capsules composed essentially of hydroxypropyl methyl cellulose.
On the other hand, it has already been known that various kinds of unit dose type receptacles and various multidose type receptacles, including medical hard capsules, have been used as receptacles for powder preparations for intratracheobronchial administration.
However, until now, it has not been a fact at all that in a powder preparation for intratracheobronchial administration, there may occur significant adhesion and/or adsorption of fine particles comprising a main medicament. It will be understood that to the present inventor's knowledge, the fact that the above adhesion adsorption phenomenon can be avoided by use of receptacles composed of hydroxypropyl methyl cellulose or the like, is novel and cannot be anticipated at all from the hitherto known literature or the like.